Human noroviruses in the Caliciviridae family are the major cause of non-bacterial epidemic gastroenteritis worldwide. Primary human norovirus infection does not elicit lasting protective immunity, a fact that could greatly affect the efficacy of vaccination strategies. Our long term goal is to elucidate the mechanisms by which noroviruses avoid the induction of protective immunity, ultimately translating this knowledge into successful vaccination approaches. Little is known regarding the pathogenesis of human noroviruses or the immune responses that control them because there has previously been no small animal model or cell culture system of infection. Data from our laboratory has defined the first small animal model of norovirus infection: We discovered the first murine norovirus (MNV), MNV-1, and demonstrated its cultivation in macrophages and dendritic cells in vitro. We have now used these unique models to examine norovirus pathogenesis and immunity. We have determined that MNV-1 is infectious orally and induces gastroenteritis, confirming the utility of this virus as a model to study human norovirus pathogenesis. Importantly, we have also determined that primary MNV-1 infection fails to afford protection to re-challenge with homologous virus. Thus, MNV-1 represents a valuable model with which to dissect the pathophysiological basis for the lack of lasting protection to human norovirus infection. Our specific hypothesis is that norovirus infection fails to induce protective mucosal immunity because the virus infects mucosal dendritic cells and prevents their full activation. Specifically, we will determine whether MNV-1 infection directly or indirectly inhibits dendritic cell activation and whether MNV-1 infection stimulates regulatory T cells. Our ultimate goal is to understand how these effects on mucosal dendritic cells prevent their stimulation of protective norovirus immunity and to translate this information into effective vaccine design.

Public Health Relevance

Human noroviruses in the Caliciviridae family are the major cause of non-bacterial epidemic gastroenteritis worldwide but infection does not induce lasting protection. Our long term goal is to elucidate the mechanisms by which norovirus infection avoids the induction of protective immunity, ultimately translating this knowledge into successful vaccination strategies. Our specific hypothesis is that norovirus infection of mucosal dendritic cells results in a partial activation of these cells leading to the induction of regulatory immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081921-04
Application #
8298615
Study Section
Virology - B Study Section (VIRB)
Program Officer
Cassels, Frederick J
Project Start
2009-09-07
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$320,652
Indirect Cost
$97,902
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611